The clinical activities of the present proposal will continue to be centered on our Clinical Facility that includes as an outpatient service, a DAY HOSPITAL that treats sickle cell anemia patients with uncomplicated painful crises, during working hours and provides support to the physicians that have hospitalized patients in Montefiore Hospital. The Clinical Facility also serves as a Pain Laboratory, (on which Project 8 will be based), with the purpose of studying the use of non-narcotic pain medication, new methods of delivery of analgesics, protocols of pain management and development of objective criterias for pain complications other than painful crises. It also serves as a resource for materials, indispensable for the research projects. Of the projects proposed, two are clinical projects: Project 17 in which we will develop a database between two outside institutions (U. of Mississippi and U. of Georgia) and our own sources of patients, to define the relationship between beta- gene cluster haplotypes and the phenotypic expression of SS disease. The size of the sample needs to be large, to extricate other confounding genetic determinants as gender and alpha-thalassemia, in addition to a rather large number of haplotype subclasses. Project 8 will look at a very daunting problems: the basis of pain recidivism in SS patients that are high utilizers of medical facilities. Efforts will be made in establishing their psychological profiles, pain strategies according their subtyping, and biological parameters of judgment as to origin of the pain. there are five research projects: Project 14, a ground breaking effort in trying to understand the SS cell interactions (adhesion vs. occlusion) in the microcirculation of the lung, kidney and retina, with regard to the specific physiological features of each organ. Organ damage has been the big forgotten subject in sickle cell anemia, and it is time to change the situation. Project 4 builds on previous efforts to analyze the structural and function properties of selected SS red cell membrane and cytoskeletal proteins and to establish whether these proteins are modified in ways that affect their function, and to define the mechanisms that result in functional abnormalities. Project 15: There is limited knowledge on the pathobiology of SC disease, and this project brings to bear our special expertise in the relation between beta-gene cluster haplotypes and HbF level expression, the basis for the abnormal red cell volume in these cells, and to better understand the role of HbC crystallization on the pathobiology of the disease. this syndrome can be cured by changing the MCHC of SC cells. Project 5: The quintal structure of the HbS polymer (that is how the HbS tetramers are arranged in fibers) is not fully understood, and this has been a drawback for the rational development of anti-sickling agents. This project will use direct and reverse proteolysis to stitch together portions of globins chains (technique already tested) to define the residues involved specially in the inter-Wishner-Love double strands. No solutions data exist to fully define these contacts. Project 16: This project is based on proponent observation that circulating BFU-E exhibit different properties according to the %HbF (and anemia) of SS patients. This heterogeneity is extended also to the response to cytokines and inhibitory factors. The definition of these interactions and its heterogeneity among SS patients will allow the potential use of cytokines, in a rational fashion, in the management of certain aspects of the disease. Education project: Project 18: The primary aim is to develop and evaluate the efficacy of a peer educational interventional program for medical personnel providing care for sickle cell anemia patients.